Rheumatoid arthritis (RA) is a common, relapsing autoimmune disease affecting 0.8-1% of the population worldwide (1) (2). RA presents clinically with joint swelling, deformity, pain, stiffness, and weakness (3). The primary sites of tissue damage are joints, but systemic involvement of the eyes, kidneys, chest and lungs may also occur (4). The rheumatoid synovial environment is an area of intense immunological activity. The cellular composition of the affected RA joint is characterized by proliferation of synovial lining cells, pannus accumulation over articular cartilage and the infiltration of inflammatory cells, including mononuclear cells and lymphocytes. Fibroblast-like synovial (FLS) cells are thought to be responsible for pannus formation and contribute to bone and cartilage destruction.
One of the hallmarks of RA is synovial hyperplasia. Two critical resident cells types in affected synovial tissue (ST) are: a CD68+/MHCII+ macrophage-like synoviocyte (MLS) and a CD68−/MHCII-FLS cell (5). The intimal layer increases from several cells to 15 cells deep, due to increased FLS cell numbers, through a combination of increased proliferation, decreased apoptosis and decreased senescence (5). FLS cells synthesize and secrete many pro-inflammatory mediators—cytokines, chemokines, growth factors—that are involved in autocrine and paracrine regulation of inflammation (5) and, therefore, are critical effectors in regulating the inflammatory response in RA. FLS cells are found in the intima and subintima, and FLS cells in RA are thought to transform into cells that proliferate in an anchorage-independent manner, lack contact inhibition and secrete cytokines constitutively. Many growth factors, such as PDGF, bFGF, TGF-β and activin are expressed in RA and drive fibroblast proliferation in vitro (6) (7) (8) (9) (10).